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Regulation of the proteasome by Fbxo7

Fbxo7 对蛋白酶体的调节

基本信息

批准号：
BB/J007846/1
负责人：
Heike Laman
金额：
$ 44.52万
依托单位：
University of Cambridge
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2012
资助国家：
英国
起止时间：
2012 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FJ007846%2F1
关键词：
Regulation proteasome Fbxo7

项目摘要

Living cells are largely constructed from a multitude of different proteins, each with their own individual functions and properties. Just like the components of any man-made machine, these proteins are susceptible to "wear and tear" and can become damaged over time. The health of a cell, and consequently the whole organism to which it belongs depends on the timely and specific removal of damaged proteins to prevent their accumulation in toxic aggregates that will eventually poison the cell. Cells have evolved a mechanism to identify and then destroy unwanted proteins, called the "ubiquitin-proteasome system". Damaged proteins are marked with chains of small ubiquitin molecules, targeting them to the proteasomes, the cell's "recycling bins". The failure of this system to clear protein aggregates has been linked to multiple human diseases, including Parkinson's disease, Alzheimer's disease, type II diabetes and is also implicated in those involving prion proteins which cause Creutzfeldt-Jakob disease in humans, BSE in cattle and scrapie in sheep and goats. Conversely, over-activity of the ubiquitin-proteasome system has been linked with various muscle atrophy diseases, it is therefore clear that proper regulation of this system is required for the maintenance of health.Recently, a study detailing the properties of a controller of the rate at which the proteasomes operate has been published. This protein, called PI31, has been shown to both increase and decrease proteasome activity under different circumstances. However, PI31 does not act alone. We have identified a protein called Fbxo7 that is not only capable of marking proteins for destruction with ubiquitin but which also binds to PI31. Studies in fruit flies have shown that this interaction enhances the ability of PI31 to regulate the proteasomes, and flies lacking their analgous Fbxo7 protein, which is called nutcracker, have reduced proteasome activity, and causes sterility in male flies. We have found that loss of the Fbxo7 in mice also affects their fertility. Furthermore, mutations in the human Fbxo7 gene have also been linked to Parkinson's disease, suggesting that Fbxo7 may also cooperate with PI31 to regulate proteasome activity in mammalian systems.We want to understand in detail how Fbxo7 participates in the regulation of proteasome activity in mammalian cells. We will use a variety of methods to investigate the relationship between PI31 and Fbxo7, determining whether the interaction between these two proteins affects their ability to regulate proteasome activity and mark proteins for degradation, respectively. We will also determine how the loss or over-representation of Fbxo7 in cells affects proteasome activity in cells using a range of assays both in cell lines and in an mouse model. By doing experiments to broaden our understanding of the protein degradation machinery, we hope to be able to affect and ultimately direct these processes in clinically relevant settings.

活细胞主要由多种不同的蛋白质构成，每种蛋白质都有自己独特的功能和特性。就像任何人造机器的组件一样，这些蛋白质很容易受到“磨损”，并且随着时间的推移可能会被损坏。细胞及其所属的整个生物体的健康取决于及时、具体地去除受损蛋白质，以防止它们积累在有毒聚集物中，最终毒害细胞。细胞已经进化出一种机制来识别然后破坏不需要的蛋白质，称为“泛素蛋白酶体系统”。受损的蛋白质被标记有小泛素分子链，将它们靶向蛋白酶体，即细胞的“回收站”。该系统未能清除蛋白质聚集物与多种人类疾病有关，包括帕金森病、阿尔茨海默病、II 型糖尿病，并且还与导致人类克雅氏病、牛疯牛病以及绵羊和山羊瘙痒症的朊病毒蛋白相关疾病有关。相反，泛素-蛋白酶体系统的过度活跃与各种肌肉萎缩疾病有关，因此很明显，为了维持健康，需要对该系统进行适当的调节。最近，一项详细介绍了蛋白酶体运行速率控制器特性的研究已经发表。这种称为 PI31 的蛋白质已被证明在不同情况下会增加和减少蛋白酶体活性。然而，PI31 并不单独行动。我们已经鉴定出一种名为 Fbxo7 的蛋白质，它不仅能够标记蛋白质以供泛素破坏，而且还能与 PI31 结合。对果蝇的研究表明，这种相互作用增强了 PI31 调节蛋白酶体的能力，而缺乏类似 Fbxo7 蛋白（称为胡桃夹子）的果蝇会降低蛋白酶体活性，并导致雄性果蝇不育。我们发现小鼠 Fbxo7 的缺失也会影响它们的生育能力。此外，人类Fbxo7基因的突变也与帕金森病有关，这表明Fbxo7也可能与PI31协同调节哺乳动物系统中的蛋白酶体活性。我们想详细了解Fbxo7如何参与哺乳动物细胞中蛋白酶体活性的调节。我们将使用多种方法来研究 PI31 和 Fbxo7 之间的关系，确定这两种蛋白质之间的相互作用是否影响它们分别调节蛋白酶体活性和标记蛋白质降解的能力。我们还将使用细胞系和小鼠模型中的一系列测定来确定细胞中 Fbxo7 的丢失或过度表达如何影响细胞中的蛋白酶体活性。通过进行实验来扩大我们对蛋白质降解机制的理解，我们希望能够在临床相关环境中影响并最终指导这些过程。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Opposing effects on the cell cycle of T lymphocytes by Fbxo7 via Cdk6 and p27.

Fbxo7 通过 Cdk6 和 p27 对 T 淋巴细胞的细胞周期产生相反的作用。

DOI：
10.17863/cam.7754
发表时间：
2017
期刊：
影响因子：
0
作者：
Patel S
通讯作者：
Patel S

The Parkinson's disease-linked proteins Fbxo7 and Parkin interact to mediate mitophagy.

帕金森病相关蛋白 Fbxo7 和 Parkin 相互作用以介导线粒体自噬。

DOI：
10.17863/cam.10001
发表时间：
2013
期刊：
影响因子：
0
作者：
Burchell V
通讯作者：
Burchell V

Study of an FBXO7 patient mutation reveals Fbxo7 and PI31 co-regulate proteasomes and mitochondria.

对 FBXO7 患者突变的研究表明，Fbxo7 和 PI31 共同调节蛋白酶体和线粒体。

DOI：
10.17863/cam.106563
发表时间：
2024
期刊：
影响因子：
0
作者：
Al Rawi S
通讯作者：
Al Rawi S

Analysis of the FBXO7 promoter reveals overlapping Pax5 and c-Myb binding sites functioning in B cells.

DOI：
10.1016/j.bbrc.2021.03.052
发表时间：
2021-05-21
期刊：
Biochemical and biophysical research communications
影响因子：
3.1
作者：
Harris R;Randle S;Laman H
通讯作者：
Laman H

Beyond ubiquitination: the atypical functions of Fbxo7 and other F-box proteins.

DOI：
10.1098/rsob.130131
发表时间：
2013-10-09
期刊：
Open biology
影响因子：
5.8
作者：
Nelson DE;Randle SJ;Laman H
通讯作者：
Laman H

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Heike Laman其他文献

Uroplakin III, a novel Sic substrate in Xenopus egg rafts, is a target for sperm protease essential for fertilization

Uroplakin III 是非洲爪蟾卵筏中的一种新型 Sic 底物，是受精所必需的精子蛋白酶的靶标

DOI：
发表时间：
2005
期刊：
Developmental Biology 286
影响因子：
0
作者：
Tomisato;W;Heike Laman;Kayoko Maehara;Sakakibara et al.;Hirose E. et al.;Sato et al.;Bravou V. et al.;Tokmakov et al.;Karakaidos P. et al.;Xouri G. et al.;Sakakibara et al.;Nishitani H. et al.;Sugimoto N. et al.;Kurokawa et al.;Mahbub Hasan et al.
通讯作者：
Mahbub Hasan et al.

Real-time in vivo imaging of p16^<Ink4a> unveils a cross talk between p53 and p16^<Ink4a>

p16^<Ink4a> 的实时体内成像揭示了 p53 和 p16^<Ink4a> 之间的串扰

DOI：
发表时间：
2009
期刊：
影响因子：
0
作者：
Laman;H.;Funes;J.;Ye;H.;Henderson;S.;Galinanes-Garcia;L.;Hara;E.;Knowles;P.;McDonald;N.;Boshoff;C.;Heike Laman;Kayoko Maehara;Naoko Ohtani;Eiji Hara;Eiji Hara
通讯作者：
Eiji Hara

Functional, biochemical, and chromatographic characterization of the complete [Ca^<2+>]_1 oscillation-inducing activity of porcine sperm

猪精子完整 [Ca^<2 >]_1 振荡诱导活性的功能、生化和色谱表征

DOI：
发表时间：
2005
期刊：
Developmental Biology 285
影响因子：
0
作者：
Tomisato;W;Heike Laman;Kayoko Maehara;Sakakibara et al.;Hirose E. et al.;Sato et al.;Bravou V. et al.;Tokmakov et al.;Karakaidos P. et al.;Xouri G. et al.;Sakakibara et al.;Nishitani H. et al.;Sugimoto N. et al.;Kurokawa et al.
通讯作者：
Kurokawa et al.

Egg fertilizome : From transmembrane signaling to translational control of gene expression in the initiation of development : In: Focus on Genome Research(Williams, C.R.ed.)

卵子受精组：从跨膜信号传导到发育起始中基因表达的翻译控制：In：聚焦基因组研究（Williams，C.R.ed.）

DOI：
发表时间：
2004
期刊：
影响因子：
0
作者：
Tomisato;W;Heike Laman;Kayoko Maehara;Sakakibara et al.;Hirose E. et al.;Sato et al.;Bravou V. et al.;Tokmakov et al.;Karakaidos P. et al.;Xouri G. et al.;Sakakibara et al.;Nishitani H. et al.;Sugimoto N. et al.;Kurokawa et al.;Mahbub Hasan et al.;Sato K.et al.;Nishitani H. et al.;西谷秀男;Tokmakov A.A.et al.;Sato K.et al.;Sakakibara K.et al.;Sakakibara K.et al.;Sato K.et al.;Kurokawa M.et al.;Kurokawa M.et al.;Sato K.et al.;Hadiarto et al.;Iwasaki et al.;Sato K.et al.
通讯作者：
Sato K.et al.

Visualizing the dynamics of Oncogenic stress response in living mice.

可视化活体小鼠致癌应激反应的动态。

DOI：
发表时间：
2009
期刊：
影响因子：
0
作者：
Laman;H.;Funes;J.;Ye;H.;Henderson;S.;Galinanes-Garcia;L.;Hara;E.;Knowles;P.;McDonald;N.;Boshoff;C.;Heike Laman;Kayoko Maehara;Naoko Ohtani
通讯作者：
Naoko Ohtani